RU2135498C1 - Pyrazolo- and pyrrolopyridines - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to the compound of the formula (I)

and pharmaceutically acceptable acid-additive salts where A means N or CH; B means -NT₁R₂,-NHCHR₁R₂,-OCHR₁R₂. Compounds show an antagonistic activity with respect to corticotropin-releasing factor (CRF). It is known that CRF-antagonists are effective for treatment of broad spectrum of diseases caused by stress, for example, depression, fear, headache, irritable bowel syndrome, inflammatory diseases, immunity attenuation, Alzheimer's disease, gastroenteric diseases, neurotic anorexia, hemorrhagic stress, abstinent syndrome of drug and alcohol withdrawal, addiction to excess use of drugs and sterility. EFFECT: enhanced effectiveness of compounds. 7 cl, 1 tbl, 8 ex

Description

 The invention relates to pyrazolopyridines and pyrrolopyridines, pharmaceutical compositions containing these compounds, and methods of their administration to a subject who needs their antagonistic activity with respect to a factor promoting the release of adrenocorticotropic hormone (corticotropin releasing factor (CRF).

 CRF antagonists related to peptides and pyrazolinones are described in US Pat. Nos. 4,605,642 and 5,063,245, respectively. The importance of antagonists is indicated in the literature, for example, it is discussed in US patent N 5063245, which is included in the list of links of this invention. A current description of the various activities possessed by CRF antagonists is given in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425-473 (1991), which is also included in the reference list of this invention. Based on the studies described in these and other references, it is believed that CRF antagonists are effective in treating a number of diseases associated with stressful situations, such as depression, fear, headache, irritable bowel syndrome, inflammatory diseases, weakened immunity, Alzheimer's disease , gastrointestinal upsets, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, addiction to excessive drug use and infertility.

и его фармацевтически приемлемым кислотно-аддитивным солям,
где A - N или CH;
B - -NR₁R₂, -NHCHR₁R₂, -OCHR₁R₂;
R₁ - C₁-C₆ алкил, который необязательно может содержать один или два заместителя, независимо выбранных из группы, включающей гидроксильную группу и C₁-C₄ алкоксигруппу;
R₄ - C₁-C₁₂ алкил;
R₃ - C₁-C₄ алкил;
R₄ - водород, C₁-C₆ алкил;
R₅ - фенил, содержащий три заместителя, представляющих собой C₁-C₆ алкил;
R₇ - водород, C₁-C₄ алкил.This invention relates to a compound of the formula

and its pharmaceutically acceptable acid addition salts,
where A is N or CH;
B is -NR ₁ R ₂ , -NHCHR ₁ R ₂ , -OCHR ₁ R ₂ ;
R ₁ is C ₁ -C ₆ alkyl, which optionally may contain one or two substituents independently selected from the group consisting of a hydroxyl group and a C ₁ -C ₄ alkoxy group;
R ₄ is C ₁ -C ₁₂ alkyl;
R ₃ is C ₁ -C ₄ alkyl;
R ₄ is hydrogen, C ₁ -C ₆ alkyl;
R ₅ is phenyl containing three substituents representing C ₁ -C ₆ alkyl;
R ₇ is hydrogen, C ₁ -C ₄ alkyl.

A group of specific embodiments of the present invention includes compounds of formula I, where (a) R ₁ represents C ₁ -C ₄ alkyl, which may optionally contain a C ₁ -C ₂ alkoxy group as a substituent, R ₂ represents C ₁ -C ₄ alkyl; or (b) R ₁ is C ₁ -C ₄ alkyl substituted with a hydroxyl group.

Another group of more specific embodiments of the present invention relates to compounds of formula I, in which: (a) R ₃ represents methyl; (b) R ₄ is hydrogen, methyl; and (c) R ₅ is phenyl containing three substituents independently selected from C ₁ -C ₆ alkyl.

Other more specific embodiments of the present invention relate to compounds of formula I, wherein R ₃ is methyl; R ₄ is hydrogen, C ₁ -C ₃ alkyl; and R ₅ is substituted phenyl.

Examples of specific embodiments of the present invention are the following compounds:
butyl- [3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] ethylamine;
[3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-piraeolo [3,4-b] pyridin-4-yl] - (1-methoxymethylpropyl) amine;
4- (1-methoxymethylpropoxy) -3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridine;
(1-ethylpropyl) - [3,5,6-trimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amine.

 The invention also includes a pharmaceutical composition for treating (a) a disease, the treatment of which can be treated or the treatment of which can be facilitated by an antagonistic effect on CRF, including, but not limited to, diseases induced by CRF or diseases caused by CRF, or (b) a disease selected from the group of inflammatory diseases, such as rheumatoid arthritis or osteoarthritis, pain, asthma, psoriasis and allergies; diseases caused by a state of fear; panic condition, phobia; compulsive compulsive disorder; post-traumatic stress state; sleep disturbances, including due to stress; pain, such as fibromyalgia; mood-related diseases such as depression, including general depression, episodic depression, recurring depression, depression caused by childhood stress (child abuse induced depression), postpartum depression; dysteias; bipolar disorders (bipolar disorders); cyclotomies; fatigue syndrome; stress headache; cancer irritable bowel syndrome; granulomatous disease, Crohn's disease; mucous colitis; human immunodeficiency virus infection (HIV infection); dementia, such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Huntington's disease); gastrointestinal disease; eating disorders such as neurotic anorexia and bulimia; hemorrhagic stress; addiction to chemicals and drugs (e.g. addiction to alcohol, cocaine, heroin, benzothiazepines, or other medicines); withdrawal syndrome on drugs and alcohol; stress episode; euthyroidism weakening syndrome, antidiuretic hormone mismatch syndrome (ADH); obesity infertility head injuries; spinal cord injuries; ischemic neuronal damage (e.g. cerebral ischemia, such as cerebral ischemia of the hypocampus (cerebral hippocampal ischemia)); excitotoxic neural lesions; epilepsy; seizure Immune dysfunctions, including stress-related dysfunctions (such as porcine stress syndrome), bovine shipping fever, equine paroxysmal fibrillation and dysfunctions caused by chicken’s “restricted movement” ( dysfunctions induced by confinement in chickens), sheep stress causing sheering stress in sheep or dog stress caused by human-animal interaction (dogs); muscle spasm; urinary incontinence; senile dementia of the Alzheimer's type (senile dementia of Aizheimer's type); dementia caused by multiple heart attacks (multiinfarct dementia); amyotrophic lateral sclerosis; hypoglycemia in a mammal, including humans; the composition comprises a compound of formula I or a pharmaceutical salt thereof in an amount providing effective treatment for such a disease, and a pharmaceutically acceptable carrier.

 The invention also includes methods of treating (a) a disease that can be treated, or that can be mediated by an antagonistic effect of CRF, including, but not limited to, diseases caused by CRF or diseases caused by CRF, or (b) diseases selected from the group of inflammatory diseases, such as rheumatoid arthritis or osteoarthritis, pain, asthma, psoriasis and allergies; diseases caused by a state of fear; panic condition; phobias; compulsive compulsive disorder; post-traumatic stress state; sleep disturbances caused by stress; pain, such as fibromyalgia; mood-related diseases such as depression, including general depression, episodic depression, recurring depression, depression caused by childhood stress, postpartum depression; distemy; bipolar disorder; cyclotomies; fatigue syndrome; stress headache; cancer irritable bowel syndrome; granulomatous disease, Crohn's disease (Crohn); mucous colitis; human immunodeficiency virus infection (HIV infection); dementia, such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Huntington's disease); gastrointestinal diseases; eating disorders such as neurotic anorexia or bulimia; hemorrhagic stress; psychotic episode caused by stress; euthyroidism weakening syndrome; antidiuretic hormone mismatch syndrome (ADH); obesity infertility head injuries; spinal cord injuries; ischemic neuronal damage (e.g. cerebral ischemia, such as cerebral hypocampal ischemia); excitotoxic neural lesion; epilepsy; seizure immune dysfunctions, including dysfunctions of the immune system caused by stress (for example, pig stress syndrome, spitting up fever of a cow, convulsive fibrillation of a horse, and dysfunctions caused by restriction of movement in a chicken, stress in a sheep causing abnormalities, or stress in dogs caused by human-animal interaction); muscle spasm; urinary incontinence; senile dementia of the Alzheimer's type; dementia caused by multiple heart attacks; amyotrophic lateral sclerosis; addiction to chemicals and drugs (e.g. addiction to alcohol, cocaine, heroin, benzothiazepines, or other medicines); withdrawal syndrome on drugs and alcohol; hypoglycemia in a mammal, including humans; treatment includes administering to a subject in need of said treatment a compound of formula I or a pharmaceutically acceptable salt thereof in an amount that provides effective treatment for such a disease.

где D представляет хлор, гидроксильную или цианогруппу;
R₉ - C₁-C₄ алкил, хлор; и
A, R₄, R₅ и R₇ принимают значения, указанные выше для формулы I.The invention also includes intermediates of the formula

where D represents chlorine, hydroxyl or cyano;
R ₉ is C ₁ -C ₄ alkyl, chloro; and
A, R ₄ , R ₅ and R ₇ take the meanings indicated above for formula I.

As used herein, the term “C ₁ -C ₆ alkyl”, unless otherwise indicated, is used to mean a straight or branched alkyl chain containing from one to six carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl or hexyl .

 The compounds of formulas I and II may contain a chiral center and, therefore, can exist in various enantiomeric forms. This invention relates to all optical isomers and stereoisomers of compounds of formulas I and II and mixtures thereof.

Compounds of formula I, wherein B is —NR ₁ R ₂ , —NHCHR ₁ R _2, or —OCHR ₁ R ₂ , can be prepared by reacting a compound of formula II wherein D is Cl and R ₄ , R ₅ , R ₇ and A take the meanings defined above for formula I, with a compound of formula BH, where B takes the meanings defined in this paragraph above, or with a compound of formula R ₁ NH ₂ . The reaction is carried out in a solvent in the presence of a base at a temperature in the range of from about room temperature to about 230 ^° C. in the presence or without an organohalogenide such as bromide, iodide or copper chloride, or magnesium bromide, in the presence or without an acid catalyst such as p- toluenesulfonic acid. Suitable solvents are organic solvents such as tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), acetone, C ₁ -C ₅ alkyl alcohol, chloroform, benzene, xylene, dioxane, toluene, sulfolane, pyridine or 1-methyl-2- pyrrolidinone. Preferably, the solvent is dimethyl sulfoxide or 1-methyl-2-pyrrolidinone.

In the case where B of the target compound of formula I is —NR ₁ R or —NHCHR ₁ R ₂ , an excess of compound BH may be used as a reagent or base. Bases other than BH may also be used, such as potassium carbonate and tri (C ₁ -C ₆ ) alkylamine. This reaction is usually carried out at a temperature of from about 75 ^° C. to about 230 ^° C. Organohalogenides, such as copper bromide, can be used to facilitate the reaction. In the case where the reaction proceeds very passively, the compounds of formula I, where B is —NR ₁ R ₂ or —NHCHR ₁ R ₂ , can be prepared in two stages, as described below. The reaction of compounds of formula II with an excess of R ₁ NH ₂ or NH ₃ or an equivalent NH ₃ precursor (e.g., NaN ₃ , n-BuN ⁺ N ₃ N ^- or NH ₂ OH) at a temperature of from about 75 ^° C to about 250 ^° C and a pressure of from about 0 to about 300 psi in a suitable solvent, as described above, gives compounds of formula I, wherein B is —NHR ₁₁ , —NH ₂ , —NH ₂ OH, or —N ₃ . The conversion of compounds of formula I, where B is —N ₃ or —NH ₂ OH, to the corresponding compounds of formula I, where B is —NH ₂ , can be carried out by known methods, such as hydrogenation or reduction. Alkylation of compounds of formula I, where B is —NHR ₁ or —NH ₂ , with a suitable alkyl halide in the presence of a suitable base such as lithium or sodium bis-trimethylsilylamide, or lithium or sodium diisopropylamide, or n-butyl lithium or sodium tert-butoxide, in a suitable solvent such as THF, dioxane or methylene chloride, will produce the corresponding compounds of formula I, where B is —NR ₁ R ₂ . According to another method, the acylation of compounds of formula I, where B is —NHR ₁ or —NH ₂ , followed by reduction with a borohydride (eg, sodium borohydride), will produce compounds of formula I, where B is —NR ₁ R ₂ .

 In the case where the reaction of BH and a suitable compound of formula II proceeds very passively, acidic conditions obtained with p-toluenesulfonic acid or phenol or its derivatives can be used.

When B is —OCHR ₁ R ₂ , it is possible to obtain a base which is capable of deprotonating BH, such bases are alkali metal hydrides such as sodium or potassium hydride, or organometallic bases such as sodium diisopropylamide, sodium bis (trimethylsilyl) amide lithium diisopropylamide, lithium or sodium bis (trimethylsilyl) amide or n-butyllithium. The solvent is preferably tetrahydrofuran, dimethyl sulfoxide, methylene chloride, toluene, sulfolane or 1-methyl-2-pyrrolidinone and the reaction is usually carried out at a temperature in the range of from about room temperature to 180 ^° C, preferably in the range of from about 50 ^° C to about 130 ^o C.

The compounds of formula II, where D is a cyano group, R ₄ , R ₅ and R ₇ are as defined above, and R ₉ is (C ₁ -C ₄ ) alkyl or chloro (hereinafter referred to as compounds of formula IIA), may be obtained by reacting the corresponding compounds of formula II, where D is chloro, with potassium cyanide or copper cyanide in the presence or without sodium p-toluenesulfonate or sodium methanesulfonate as a catalyst in dimethyl sulfoxide or N, N-dimethylformamide.

Compounds of formula II where N is, D is OH and R ₉ is C ₁ -C ₄ alkyl can be prepared according to Scheme 1 by reacting a compound of formula IV with a compound of formula III in the presence of an acid catalyst such as p-toluenesulfonic acid, HCl or H ₂ SO ₄ , in a suitable solvent, such as toluene, benzene or xylene, with a Dean-Stark trap, at a temperature in the range of about 60 to 150 ^° C., preferably when refluxed. Compounds of formula IV can be prepared by acid hydrolysis of the corresponding compounds of formula V at reflux temperature.

Suitable acids are 85% phosphoric acid, aqueous HCl and aqueous H ₂ SO ₄ . Compounds of formula V can be prepared as described in Serial N PCT / US 93/11333, filed in the United States, or by known methods, simultaneously filed November 26, 1993. International application PCT / US 93/11333 is included in the reference list of this invention.

 Scheme 1.

Соединения формулы I, где R₇ является алкильной группой, можно получать через промежуточный продукт формулы IIB или соединение формулы ID, где R₇ представляет -COOR, -COR или CN, как показано на Схеме 2, превращением группы R₇ в другие группы R₇ с использованием общеизвестных методов. Например, гидролиз соединения, в котором R₇ представляет собой сложный эфир, с основанием (например, гидроксидом лития в смеси вода: диоксан 1:1 или вода: метанол 1: 1 или водным LiOH или NaOH) при температуре в интервале примерно от 80^oC до 100^oC, с последующим гашением реакции кислотой и кипячением с обратным холодильником для осуществления декарбоксилирования, приводит к соответствующему соединению формулы ID, где R₇ - H. Восстановление соединений, в которых R₇ является сложно-эфирной группой, при помощи восстановителя, такого как LiAlH₄ или гидрида диизобутилалюминия, приводит к получению соответствующих соединений, в которых R₇ представляет собой CH₂OH или CHO. Алкилирование CH₂OH группы с основанием, таким как NaH, алкоксид натрия или литийорганические производные, с последующим алкилированием метилиодидом или этилиодидом, приводит к получению соединений формулы ID, где R₇ - -CH₂OCH₃ или -CH₂OC₂H₅. Реакция Гриньяра группы -CO₂CH₃, -CO₂C₂H₅, -COCH₃ или -COC₂H₅ с последующим элиминированием и гидрированием приводит к получению соединений формулы ID, где R₇ представляет собой алкильную группу. В описанном выше синтезе для получения целевых соединений может использоваться метод введения защитных групп с последующим их удалением.

Compounds of formula I where R ₇ is an alkyl group can be prepared via an intermediate of formula IIB or a compound of formula ID, where R ₇ is —COOR, —COR or CN, as shown in Scheme 2, by conversion of R ₇ to other R ₇ groups using well-known methods. For example, hydrolysis of a compound in which R ₇ is an ester, with a base (for example, lithium hydroxide in a mixture of water: dioxane 1: 1 or water: methanol 1: 1 or aqueous LiOH or NaOH) at a temperature in the range of about 80 ^o C to 100 ^o C, followed by quenching of the reaction with acid and boiling under reflux for decarboxylation, leads to the corresponding compound of formula ID, where R ₇ - H. Reduction of compounds in which R ₇ is an ester group using a reducing agent, such as LiAlH ₄ or hydride di- obutilalyuminiya affords the corresponding compounds in which R ₇ is CH ₂ OH or CHO. Alkylation of a CH ₂ OH group with a base such as NaH, sodium alkoxide or organolithium derivatives, followed by alkylation with methyl iodide or ethyl iodide, yields compounds of formula ID, where R ₇ is —CH ₂ OCH ₃ or —CH ₂ OC ₂ H ₅ . The Grignard reaction of the group —CO ₂ CH ₃ , —CO ₂ C ₂ H ₅ , —COCH ₃ or —COC ₂ H ₅ , followed by elimination and hydrogenation, yields compounds of formula ID, where R ₇ represents an alkyl group. In the synthesis described above, the method of introducing protective groups with their subsequent removal can be used to obtain the target compounds.

 Scheme 2.

Еще один способ получения соединений формулы IIB, в которых D представляет собой гидроксильную группу, хлор или цианогруппу, представлена на Схеме 3.

Another way to obtain compounds of formula IIB, in which D represents a hydroxyl group, chlorine or cyano group, is presented in Scheme 3.

 Scheme 3.

Соединения формулы VIII, где L и L' являются подходящими удаляемыми группами, такими как хлор, бром, мезил, тозил или метоксигруппа, могут превращаться в соединение формулы IX, где D - гидроксильная группа или L', при помощи реакции с амином формулы R₅NH₂ в присутствии каталитического количества кислоты, такой как п-толуолсульфокислота или серная кислота, или основание, которое способно депротонировать R₅NH₂, такое как н-бутиллитий или органогалогенид, такой как бромид, хлорид или иодид меди или бромид магния. Реакцию можно проводить в присутствии или без подходящего растворителя, в качестве которого могут использоваться спирт (например, пентанол), ДМСО, сульфолан или диоксан. Алкилирование соединений формулы IX для введения R₄ можно проводить удобными способами. Предпочтительно, процесс проводят сначала добавлением основания, такого как гидрид натрия или калия, помещенного в инертный растворитель, такой как эфир, например, диэтиловый эфир, ТГФ или диоксан, или полярный апротонный растворитель, такой как ДМСО, под атмосферой инертного газа, например азота, до получения соединения формулы IX, а затем добавляют соединение формулы R₄L, где L принимает значения, определенные выше. Температура реакции, предпочтительно, заключается в интервале от приблизительно 0^oC до приблизительно 25^oC. В том случае, когда R₄ - галоген, R₄L представляет собой галогенирующий агент, такой как бром, хлор, иод, диэтиламино сера трифторид или N-бромсукцинимид. Соединения формулы X, где R₄ - тиофенил, которые могут быть получены взаимодействием соединений формулы IX с фенил-S-SO_n-фенилом, где n=0, 1 или 2, далее могут превращаться в соединения формулы X, где R₄ - C₁-C₆ алкил, при взаимодействии с C₁-C₆ алкилиодидом с последующим восстановлением тиофенильной группы никелем Ренея или триметилсилилхлоридом (ТМСХ) с цинком для получения селективно монозамещенного соединения формулы X.

Compounds of formula VIII, where L and L 'are suitable leaving groups, such as chloro, bromo, mesyl, tosyl or methoxy, can be converted to a compound of formula IX, where D is a hydroxyl group or L' by reaction with an amine of formula R ₅ NH ₂ in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid or sulfuric acid, or a base that is capable of deprotonating R ₅ NH ₂ , such as n-butyllithium or an organ halide such as copper bromide, chloride or iodide or magnesium bromide. The reaction can be carried out in the presence or absence of a suitable solvent, which can be alcohol (for example, pentanol), DMSO, sulfolane or dioxane. Alkylation of compounds of formula IX for the introduction of R ₄ can be carried out conveniently. Preferably, the process is carried out first by adding a base, such as sodium or potassium hydride, placed in an inert solvent, such as ether, for example diethyl ether, THF or dioxane, or a polar aprotic solvent, such as DMSO, under an inert gas atmosphere, such as nitrogen, to obtain a compound of formula IX, and then add a compound of formula R ₄ L, where L is as defined above. The reaction temperature preferably ranges from about 0 ^° C. to about 25 ^° C. When R ₄ is halogen, R ₄ L is a halogenating agent such as bromine, chlorine, iodine, diethylamino sulfur trifluoride or N β-bromosuccinimide. Compounds of formula X, where R ₄ is thiophenyl, which can be prepared by reacting compounds of formula IX with phenyl-S-SO _n- phenyl, where n = 0, 1 or 2, can then be converted to compounds of formula X, where R ₄ is C ₁ -C ₆ alkyl by reaction with a C ₁ -C ₆ alkyl iodide followed by reduction of the thiophenyl group with Raney nickel or trimethylsilyl chloride (TMSC) with zinc to obtain a selectively monosubstituted compound of formula X.

Compounds of formula IIB in which R ₆ is hydrogen can be formed from compounds of formula X by reduction, for example, lithium aluminum hydride, diisobutyl aluminum hydride, followed by elimination or dehydrogenation.

 Acid addition salts are prepared conveniently by treating a solution or suspension of the free base of a compound of formula I with one chemical equivalent of a pharmaceutically acceptable acid. Convenient methods of concentration or recrystallization are used to isolate salts. Typical suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfonic acids, such as methanesulfonic, benzenesulfonate and benzene from them acid, sulfamic.

 The active compounds of this invention (compounds of formula I and their pharmaceutically acceptable salts) may be administered alone or in combination with pharmaceutically acceptable carriers, in a single dose or in multiple doses. Suitable pharmaceutically acceptable carriers are solid excipients or diluents, a sterile aqueous solution, and various organic and inorganic solvents. The pharmaceutical compositions obtained by combining the new compounds of formula I and pharmaceutically acceptable carriers are then readily administered in various dosage forms such as tablets, powders, lozenges, syrups, injectable solutions, and the like. These pharmaceutical compositions may, if necessary, contain additional ingredients such as flavorings, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, with various disintegrating agents such as starch, methyl cellulose, alginic acid and some silicon complex compounds, in combination with binders, can be used, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, binders such as magnesium stearate, sodium lauryl sulfate and talc are often used. Solid compositions of a similar type can be used as fillers in soft and hard gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are required for oral administration, the main active ingredient in them can be combined with various sweetening or flavoring agents, colorants and, if necessary, emulsifying or suspending agents in combination with fillers such as water, ethanol, propylene glycol, glycerin and mixtures thereof.

 For parenteral administration, solutions of the active active ingredient of this invention in sesame or peanut oil, aqueous propylene glycol or in a sterile aqueous solution can be used. Such aqueous solutions should contain suitable buffering agents, if necessary, and a liquid filler with a sufficient salt or glucose content to make the solution isotonic. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium used is readily prepared by standard methods known to the skilled person.

 The effective dose for the active substances of this invention depends on the chosen route of administration, as well as other factors, such as the age and weight of the patient, which are known to the attending physician. The dosage also depends on the disease to be treated. The daily dose for the treatment of diseases caused by stressful situations will, in general, be in the range from 0.1 to 50 mg / kg of the weight of the patient who needs treatment, for the treatment of inflammatory diseases, the required dose is in the range from about 0, 1 to about 50 mg / kg, for the treatment of Alzheimer's disease, from about 0.1 to about 50 mg / kg, for gastrointestinal diseases, from about 0.1 to about 50 mg / kg, for neurotic anorexia, from approximately But 0.1 to about 50 mg / kg, for the treatment of hemorrhagic stress, from about 0.1 to about 50 mg / kg, for the treatment of withdrawal symptoms for drugs and alcohol, from about 0.1 to about 50 mg / kg.

 The active compounds of this invention will generally be administered from one to three times per day (i.e., from one to three doses per day) at a dose of about 0.1 to about 100 mg / kg of patient weight, although depending on the weight and condition of the patient, the nature and severity of the disease that the patient suffers, and especially the route of administration, it will be necessary to adjust this dose. However, the dosage level, which ranges from 1.0 mg to about 50 mg per kg of patient weight, based on a single dose, will be used most often. However, changes in dosage may occur depending on the type of mammal to be treated, and the individual response of the subject to the indicated drug, as well as the type of pharmaceutical composition selected, the period of use and the time interval during which such administration is carried out.

Methods for determining the CRF antagonistic activity of a compound of formula I and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1656 (1985) and Peptides, 10, 179-188 (1985). The binding activities of the compounds of formula I, expressed as IC ₅₀ values, are shown in the table.

The following examples illustrate the preparation of the compounds of this invention. Melting points are uncorrected. NMR data are given in ppm δ (ppm) and refer to the deuterium signal from the solvent sample (deuterochloroform, unless otherwise indicated). Specific rotation was measured at room temperature using the sodium D line (589 nm). Commercial reagents were used without further purification. THF stands for tetrahydrofuran; DMF stands for dimethylformamide. Chromatography refers to column chromatography performed using 32-63 μm silica gel under an atmosphere of compressed nitrogen (fast chromatography). The room temperature or ordinary temperature indicates a temperature of 20-25 ^o C. All non-aqueous reactions are carried out under nitrogen atmosphere for convenience and to obtain maximum yield. Concentration (evaporation) of the solution is carried out using a rotary evaporator.

 Example 1. (1-Ethylpropyl) - [3,5,6-trimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] amine.

A mixture of 4-chloro-3,5,6-trimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridine (227 mg, 0.72 mmol), p-TsOH (124 mg) and ethylpropylamine (0.5 ml) in 1 ml of dimethyl sulfoxide (DMSO) are heated and refluxed for 4 hours (thin layer chromatography indicates no reaction). Copper bromide (40 mg) was added to the resulting mixture and the reaction mass was refluxed for an additional 15 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (EtOAc). The organic layer was washed with brine, dried and evaporated to give a brown oil. The oil is purified by column chromatography (silica gel, eluent: chloroform (CHCl ₃ ): hexane = 8: 3), and the title compound is obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) 6.92 (s, 2H), 3.97 (d, 1H, NH), 3.56 (br s, 1H, OH), 2.70 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 1.89 (s, 6H), 1.4-1.7 (m, 4H), 0.94 (t, 6H) ppm.

The compound is obtained in the form of the corresponding hydrochloric acid salt after recrystallization from a mixture of ethyl ether and ethyl acetate in the form of whitish crystals, mp. 201-205 ^o C.

 Example 2. Butyl- [3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] ethylamine.

A mixture of 4-chloro-3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridine (98 mg, 0.33 mmol) and N-boogylamine (1 ml) in DMSO (2 ml) is heated in an oil bath to a temperature of 175-180 ^o C and maintained at this temperature for 20 hours. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated to a brown oil. The oil residue is purified by column chromatography (silica gel; eluent: EtOAc / Hexane = 1/9) to give a colorless oil.

¹ H-NMR (CDCl ₃ ) 6.92 (s, 2H), 6.29 (s, 1H), 3.42 (q, 2H,), 3.27 (t, 2H), 2.65 (s, 3H), 2.44 (s, 3H ), 2.30 (s, 3H), 1.91 (s, 6H), 1.57 (m, 2H), 1.33 (m, 2H), 1.13 (t, 3H), 0.90 (t, 3H) ppm.

IR (neat) 2960, 2920, 1570 cm ^-1 .

 High resolution mass spectrometry (MS): calculated 364.2627; found 264.26306.

 Example 3. 2- [3,6-Dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-ylamino] butan-1-ol.

A mixture of 4-chloro-3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridine (380 mg, 1.27 mmol), (S) -2 -amino-1-butanol (0.9 ml) in DMSO (2 ml) is heated in an oil bath to a temperature of 190 ^o C and maintained at this temperature for 20 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated to a brown oil, which was then purified by column chromatography (silica gel, eluent: EtOAc / Hexane = 1/9) to give the title compound as a yellow oil, 113 mg.

¹ H-NMR (CDCl ₃ ) 6.9 (s, 2H), 5.95 (s, 1H), 4.94 (d, 1H,), 3.70 (m, 2H), 3.52 (m, 1H), 2.62 (s, 3H) , 2.40 (s, 3H), 2.28 (s, 3H), 1.92 (s, 3H), 1.90 (s, 3H), 2.6-2.8 (m, 2H), 1.0 (t, 3H), ppm.

 Example 4. 2- [3,6-Dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-ylamino] butan-1-ol and 3.6 -dimethyl-4-phenoxy-1- (2,4,6-trimethyl-phenyl) -1H-pyrazolo [3,4-b] pyridine.

A mixture of 4-chloro-3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridine (300 mg, 1 mmol), (3) -2-amino -1-butanol (107 mg, 1.2 mmol) and phenol (188 mg, 2 mmol) are heated in an oil bath to 190 ^o C and kept at this temperature for 15 hours. The mixture is cooled, quenched with 2N sodium hydroxide solution and extracted with chloroform. The organic fraction was separated and neutralized with 2N hydrochloric acid and water. The organic fraction was dried and evaporated to a residue as an oil. The residue was purified by column chromatography (silica gel, chloroform eluent) to obtain 157 mg of the starting material and 52 mg of 3,6-dimethyl-4-phenoxy-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3, 4-b] pyridine in the form of beige crystals.

¹ H-NMR (CDCl ₃ ) 7.1-7.45 (m, 5H), 6.95 (s, 2H), 6.06 (s, 1H), 2.71 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H ), 1.94 (s, 6H) ppm;
and 30 mg of 2- [3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-ylamino] butan-1-ol in the form of a glassy substance yellow color.

 Example 5. [3,6-Dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridin-4-yl] - (1-methoxymethylpropyl) amine.

 Solution 2- [3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-ylamino] butan-1-ol (69 mg, 0.196 mmol ) in 1 ml of dry tetrahydrofuran is treated with 60% sodium hydride in oil (28 ml, 0.7 mmol). After stirring for 3 minutes, methyl iodide (0.3 ml) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was quenched with water and extracted with ether. The organic fraction was washed with water, dried and evaporated to give 61 mg of a technical product. The residue was purified by column chromatography (silica gel, eluent: chloroform) to give 43 mg of the title compound as a yellow glassy substance.

¹ H-NMR (CDCl ₃ ) 6.91 (s, 2H), 6.00 (s, 1H), 5.05 (d, 1H), 3.4-3.6 (m, 2H), 3.41 (s, 3H), 2.66 (s, 3H ), 2.40 (s, 3H), 2.28 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.6-1.8 (m, 2H), 1.05 (t, 3H) ppm.

IR (CHCl ₃ ) 2920, 1585 cm ^-1 ; High resolution MC: calculated 366.2413; found 366.24516.

 The compound, which is a glassy substance, is converted into the corresponding salt of hydrochloric acid, which is a yellow solid.

 Example 6. 4- (1-Methoxymethylpropoxy) -3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridine.

Sodium hydride (60% in oil, 94 mg, 1.33 mmol) is washed with hexane and suspended in 2 ml of tetrahydrofuran (THF). 1-Methoxy-2-butanol (0.7 ml) was added and the mixture was stirred at room temperature for 5 minutes. Then, a solution of 4-chloro-3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridine (200 mg, 0.665 mmol) in 1 ml of THF is added and the mixture was refluxed for 15 hours, then the mixture was quenched with water and extracted with EtOAc. The organic fraction was dried and evaporated to give a technical product (201 mg) as a yellow solid. The solid is purified by column chromatography (silica gel, eluent: 1% methanol in chloroform), resulting in 175 mg of light crystals, so pl. 108-108 ^o C. IR (KBr) 2900, 1600, 1580 cm ^-1 . High Resolution MS, calculated 367.2253, found 367.22754;
¹ H-NMR (CDCl ₃ ) 6.93 (s, 2H), 6.34 (s, 1H), 4.59 (m, 1H), 3.64 (2 ABq series, 2H), 3.41 (s, 3H,), 2.64 (s , 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.91 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H), 1.7 -1.9 (m, 2H), 1.04 ( t, 3H) ppm

 Example 7. 3,6-Dimethyl-4- (tetrahydrofuran-3-yloxy) -1- (2,4,6-trimethylphenyl) -1H-piraeolo [3,4-b] pyridine.

Sodium hydride (60% in oil, 176 mg, 4.4 mmol) is washed with hexane and suspended in 2 ml of tetrahydrofuran. 3-Hydroxytetrahydrofuran (1 ml) was added to the resulting mixture and stirred at room temperature for 5 minutes. After this, a solution of 4-chloro-3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo [3,4-b] pyridine (200 mg, 0.665 mmol) in 1 ml of THF is added and the resulting the mixture is refluxed with stirring for 8 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic fraction was dried and evaporated to obtain 334 mg of a technical product, and the technical product was purified by column chromatography (silica gel, eluent: 1% CH ₃ OH in CHCl ₃ ) to give 127 mg of a brown solid, mp 117-119 ^o C. IR (KBr) 2950, 1600, 1580 cm ^-1 . High Resolution MS, calculated 351.1941, found 351.19386;
¹ H-NMR (CDCl ₃ ) 6.90 (s, 2H), 6.15 (s, 1H), 5.07 (m, 1H), 3.9-4.05 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H ), 2.38 (s, 3H), 2.2-2.3 (m, 2H), 1.98 (s, 3H), 1.96 (s, 3H) ppm.

 Example 8. 1- [3,6-Dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-yl] propan-1-one.

A solution of 3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo- [3,4-b] pyridin-4-carbonitrile (200 mg, 0.690 mmol) in 1 ml of benzene is added to a solution of ethyl magnesium bromide (1M, 1.5 ml, 1.5 mmol) in 4 ml of benzene at room temperature after stirring at room temperature for 10 minutes. The reaction mixture was quenched with 2n. hydrochloric acid and stirred for 5 minutes, treated with water, neutralized with 2n. sodium hydroxide and extracted with ethyl acetate. The organic fraction was dried and evaporated to give a yellow oil. The yellow oil was purified by column chromatography (silica gel, eluent: 5% EtOAc in hexane) to give 118 mg of the title compound as a yellow solid, mp. 117-118 ^o C;
IR (KBr) 2980, 2923, 1691, 1573, 1502.

Claims (7)

1. Pyrazolo- and pyrrolopyridines of the general formula I

in which A is N or CH;
B is -NR ₁ R ₂ ; -NHCHR ₁ R ₂ ; -OCHR ₁ R ₂ ;
R ₁ - (C ₁ -C ₆ ) alkyl, which optionally may contain one or two substituents independently selected from the group consisting of a hydroxyl group and a (C ₁ -C ₄ ) alkoxy group;
R ₂ - (C ₁ -C ₁₂ ) alkyl;
R ₃ - (C ₁ -C ₄ ) alkyl;
R ₄ is hydrogen, (C ₁ -C ₆ ) alkyl;
R ₅ is phenyl containing three substituents being (C ₁ -C ₆ ) alkyl,
R ₇ is hydrogen, (C ₁ -C ₄ ) alkyl,
and their pharmaceutically acceptable acid addition salts. 2. The compound according to claim 1, where R ₁ - (C ₁ -C ₄ ) alkyl, which optionally may contain one substituent selected from a hydroxy or C ₁ -C ₂ alkoxy group; R ₂ - (C ₁ -C ₆ ) alkyl. 3. The compound according to claim 1, where R ₁ - (C ₁ -C ₄ ) alkyl containing as a substituent a hydroxyl group. 4. The compound according to claim 1, where R ₃ is methyl. 5. The compound according to claim 1, where R ₄ is hydrogen or methyl. 6. The compound according to claim 1, where: a) R ₃ is methyl; b) R ₄ is hydrogen or methyl; and c) R ₅ is phenyl containing three substituents, which are methyl. 7. The compound according to claim 1, which represents
butyl- [3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo (3,4-b) pyridin-4-yl] ethylamine;
[3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo (3,4-b) pyridin-4-yl] - (1-methoxymethylpropyl) amine;
4- (1-methoxymethylpropoxy) -3,6-dimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo (3,4-b) pyridine,
(1-ethylpropyl) - [3,5,6-trimethyl-1- (2,4,6-trimethylphenyl) -1H-pyrazolo (3,4-b) pyridin-4-yl] amine.

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